Un évênement clé dans la progression du cancer est découvert.

Columbia University Medical Center (CUMC) researchers have discovered a molecular mechanism that reprograms tumor cells in patients with advanced prostate cancer, reducing their response to anti-androgen therapy. The findings, based on a study in mice, could help to determine which patients should avoid anti-androgen therapy and identify new treatments for people with advanced prostate cancer.

The study was published online April14th in the journal Cancer Discovery.

Since androgens (male hormones) are known to drive prostate cancer, patients with recurrent or advanced disease are typically treated with anti-androgen medications. However, most patients fail treatment and develop an aggressive form of prostate cancer known as castration-resistant prostate cancer, or CRPC.

"It's been a mystery why some patients do not respond to anti-androgens, and why a subset of these patients actually get worse after treatment," said study co-leader Cory Abate-Shen, PhD, the Michael and Stella Chernow Professor of Urological Oncology and professor of urology, medicine, systems biology, and pathology and cell biology at CUMC. "Our findings show that in many of these patients, the tumor cells are reprogrammed so that they are no longer dependent on androgens."

To learn about the molecular mechanisms that drive resistance to anti-androgens, Drs. Abate-Shen and Michael Shen co-led a team to develop a strain of mice that lack two tumor-suppressor genes, Trp53 and Pten. These genes are both mutated in about 25 percent of patients with advanced prostate cancer. Mice that were treated with the anti-androgen drug abiraterone failed to respond and had accelerated tumor growth -- similar to some humans with advanced prostate cancer who do not respond to anti-androgen therapy.

"We found a number of genes that were overexpressed in mice with CRPC and also conserved in patients with the disease. Among the most interesting of these was SOX11, which regulates the development of the nervous system," said study co-leader Michael M. Shen, PhD, professor of medical sciences at CUMC.

Most localized, slow-growing prostate cancers are largely composed of epithelial cells, which are rich in androgen receptors that increase their susceptibility to anti-androgen therapy. In contrast, aggressive prostate cancers, particularly those that fail treatment, often contain many neuroendocrine-like cells, which lack androgen receptors and are therefore less responsive to anti-androgen therapy.

"This raised the question, where are the neuroendocrine-like cells in prostate tumors coming from?" said Dr. Abate-Shen. "While previous research hinted that epithelial tumor cells may be reprogrammed to become neuroendocrine-like cells, our study provides the first direct evidence that this reprogramming is actually occurring and that it is mediated, at least in part, by SOX11."

The researchers also demonstrated that SOX11 acts in a similar fashion in human prostate cancer cells.

"By giving anti-androgens to patients with CRPC, we are eliminating the cancer cells that need androgen to survive and enriching the tumor with the remaining neuroendocrine-like cells. The net effect is to create an even more aggressive tumor," said Dr. Shen.

The researchers also identified several "master regulators" -- genes that control SOX11 and other genes involved in prostate cancer reprogramming -- that might be targeted for new prostate cancer treatments.

"Based on our findings, genetic testing to identify SOX11 and the master regulators may be considered before embarking on anti-androgen therapy for patients with advanced prostate cancer," said Dr. Shen.

A University of Houston (UH) scientist and his team are working to develop the next generation of prostate cancer therapies, which are targeted at metabolism.

With approximately one out of six American men being diagnosed and nearly a quarter of a million new cases expected this year, prostate cancer is the most common malignancy among men in the U.S. Since prostate cancer relies on androgens for growth and survival, androgen ablation therapies are the standard of care for late-stage disease. While patients initially respond favorably to this course of treatment, most experience a relapse within two years, at which time limited treatment options exist. At this stage, known as castration-resistant prostate cancer, androgen-deprivation therapies are no longer effective, but interestingly, androgen receptor signaling is still active and plays a large role in the progression of the cancer. Because of this, both androgen receptors and the processes downstream of the receptor remain viable targets for therapeutic intervention. Unfortunately, it is unclear which specific downstream processes actually drive the disease and, therefore, what should be targeted.

Daniel Frigo, an assistant professor with the UH Center for Nuclear Receptors and Cell Signaling (CNRCS), has set his sights on a particular cascade of biochemical reactions inside the cell. Focusing specifically on an enzyme known as AMPK, which is considered a master regulator of metabolism, Frigo and his team have demonstrated that androgens have the capacity to take control of this enzyme's molecular signals.

"The androgen signaling cascade is important for understanding early and late-stage prostate cancer progression," Frigo said. "We found that when androgens activated this signaling pathway, it hijacked normal conditions, allowing the tumor to use diverse nutrients to the detriment of the patient. These results emphasize the potential utility of developing metabolic-targeted therapies directed toward this signaling cascade for the treatment of prostate cancer, and we look forward to exploring this and other metabolic pathways further in order to develop the next generation of cancer therapies."

In their studies, Frigo's team showed that prostate cancer cells respond to androgens not only by increasing the breakdown of sugars, a process known as glycolysis that is commonly seen in many cancers, but also escalating the metabolism of fats. While much of the research on cancer metabolism has historically focused on glycolysis, the researchers say it's now becoming apparent that not all cancers depend solely on sugars.

Their findings further indicate that the metabolic changes brought about by the AMPK enzyme result in distinct growth advantages to prostate cancer cells. They say, however, that our understanding of how androgen receptor signaling impacts cellular metabolism and what role this has in disease progression remains incomplete.

The Frigo lab is one of several within the CNRCS concentrated on the role of nuclear receptors in cancer prevention and treatment, and his team has long studied the androgen receptor, which turns on or off various signaling pathways. Frigo believes these pathways hold the potential for better cancer treatments. Targeting these underexplored metabolic pathways for the development of novel therapeutics, Frigo's ultimate goal is to unlock more effective and less harmful cancer treatment alternatives.

With funding from the Department of Defense, National Institutes of Health, Texas Emerging Technology Fund and Golfers Against Cancer, Frigo's latest research appears in Nature's Oncogene. One of the world's leading cancer journals, Oncogene covers all aspects of the structure and function of genes that have the potential to cause cancer and are often mutated or expressed at high levels in tumor cells.

The shift from androgen-dependent to androgen-independent cell growth occurs, in part, because the androgen receptor switches on an entirely different set of genes in the latter group than in the former, the researchers report in the July 24 issue of Cell. In contrast to androgen-dependent prostate tumors, androgen-independent ones experience an uptick in the activity of genes that control cell division, or mitosis. One such gene, called UBE2C, which causes cells to ignore a natural pause in the division process, becomes especially active, the researchers report. This pause, or "checkpoint," ensures that cell division progresses normally; without it, daughter cells may grow even more aggressively and be harder to stop.

"The evolution of prostate cancer from an androgen-dependent state to an androgen-independent one is a key step in its progression," says study senior author Myles Brown, MD, of Dana-Farber. "The discovery that the androgen receptor directs a distinct gene pathway in androgen-independent prostate cancers may lead to the identification of genes in that pathway that can be targeted by future therapies." Prostate cancers whose growth is fed by androgen are commonly treated with androgen-blocking drugs. Such medications can hold the disease in check for a period of time that varies from patient to patient, but the tumor almost invariably gains the ability to grow without external androgen.

One of the ways such cells re-start their growth is by producing their own androgen, scientists have discovered. Another way involves the androgen receptor itself – the "keyhole" in the cell nucleus that androgen molecules fit into – but the actual mechanism by which it operates hasn’t been known.

To find that mechanism, Brown’s team, including co-lead authors Qianben Wang, PhD, now of Ohio State, and Wei Li, PhD, now of Baylor College of Medicine, charted the activity levels, or expression, of genes controlled by the androgen receptor in androgen-dependent and androgen-independent prostate cancer cells. In the androgen-independent cells, they found a group of genes with epigenetic markings – tiny attachments to DNA that switchs genes on and off – that caused them to be especially active. The genes form a completely separate pathway from the one active in androgen-dependent cells.

It’s not known what causes those epigenetic changes to occur, but "we are profiling the genome-wide epigenetic landscape of androgen-dependent and -independent cancers, trying both experimental and computational methods to identify additional regulators," says study co-senior author X. Shirley Liu, PhD, of Dana-Farber.

"The androgen receptor clearly works by an entirely different program in androgen-dependent and -independent cancers," says Wang. "Having discovered that program, we’ll be in a better position to understand how it operates and how gene-targeted therapies may shut it down."

(Feb. 26, 2010) — Monash University biomedical scientists have identified a new way to treat castrate resistant cells in prostate cancer sufferers -- the most common cancer in Australian men.

For more than 60 years the main way to treat men with prostate cancer has involved removing the hormones that fuel growth of the cancer cells. Although initially effective this treatment inevitably fails and when the tumour growth resumes, the disease in incurable. The team, from the Prostate & Breast Cancer Research Program, has discovered a way to treat these potentially fatal diseased cells, which remain in a patient after they have undergone hormone treatment.The findings have been published in the medical journal PNAS.

Associate Dean, Research Centres & Institutes and co-author Professor Gail Risbridger said the studies provided proof of the controversial concept that estrogens (hormones mainly thought as being important for women) could be good for men and used therapeutically to treat prostate cancer.

"The research showed that drugs that activate one of the two estrogen receptors, causes cell death. Most commonly cell death in patients with prostate cancer is achieved by withdrawing androgens (male hormones) which results in castration," Professor Risbridger said.

"Although the bulk of the tumour is removed by castration, some cells remain and these castrate-resistant cells are the ones that give rise to recurrent incurable disease"The team used a drug developed to selectively and specifically activate the beta estrogen receptor in the prostate.

"It not only inhibits the growth of prostate cancer but also kills off cancer cells that are resistant to conventional treatment such as androgen deprivation therapy, more commonly known as castration therapy and does so using a mechanism that is different to castration." Professor Risbridger said.

The team made the discovery in animal models, and then successfully replicated laboratory results using human cells and tissues from patients with prostate cancer.

"The team at Monash University has discovered how this compound working through the beta receptors targets a small, but very important, population of cells in the tumour. It is a significant piece of the puzzle that will help medical research in this field -- an achievement that could eventually enhance treatment options for patients around the world with advanced prostate cancer." Professor Risbridger said.

Prostate cancer is the most common cancer in Australian men and is the second most common cause of cancer deaths in men. Each year in Australia, close to 3,300 men die of prostate cancer -- equal to the number of women who die from breast cancer annually. About 20,000 new cases are diagnosed in Australia every year and one in nine men will develop prostate cancer in their lifetime. Current treatments of prostate cancer include hormone therapy however patient side effects can be devastating.

"This research also has personal meaning and provides me with the imperative to conduct basic biomedical research where the fundamental outcomes such as those we describe, may ultimately translate into more effective ways to treat prostate cancer" Professor Risbridger said.

(July 23, 2009) — A study led by researchers at the Ohio State University Comprehensive Cancer Center and Dana-Farber Cancer Institute reveals how late-stage, hormone-independent prostate tumors gain the ability to grow without need of hormones.

The onset of hormone-independent growth marks an advanced and currently incurable stage of prostate cancer.

The study, published in the July 24, 2009, issue of the journal Cell, focuses on androgen receptors, molecules located in the nucleus of cells of the prostate gland and other tissues. Male sex hormones – androgens – bind with these receptors to activate genes that control cell growth.

The researchers show that in androgen-independent prostate cancer, androgen receptors are reprogrammed to regulate a group of genes involved in a different, later, phase of cell division, triggering rapid cell growth. They further show that a modification of a chief component of the chromosome is responsible for this reprogramming.

"Some late-phase prostate cancer does not require androgen hormones for tumor growth, but it does require androgen receptors," says first author and co-corresponding author Qianben Wang, assistant professor of molecular and cellular biochemistry and a researcher with the Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute.

"Our study reveals the role of androgen receptors in hormone independent prostate cancer, how they become active in that disease and what genes they regulate to promote tumor growth."

The findings provide a better understanding of prostate cancer and could identify new therapeutic targets and lead to new treatments for this lethal stage of the disease, he says.

Prostate cancer is the most frequently diagnosed cancer in men. An estimated 192,280 new cases are expected in the United States in 2009, along with 27,360 deaths from the disease.

To conduct the study, Wang working with corresponding author Dr. Myles Brown, professor of medicine at Harvard Medical School and Dana-Farber Cancer Institute, and a group of colleagues used hormone-dependent and hormone independent prostate cancer cell lines, gene expression data and tissue from human tumors.

They showed that in hormone-dependent disease, androgen receptors regulate an early phase of cell cycle. In hormone-independent prostate cancer, however, the receptors are reprogrammed to selectively regulate genes involved in actual cell division, that is, the mitotic phase of the cycle.

A gene called UBE2C was a standout among these genes, and increased expression of that gene correlated with progression to the hormone-independent phase.

Furthermore, a chemical change – an epigenetic change – in a histone protein associated with that gene enabled androgen receptors to bind with and activate the gene in hormone-independent prostate cancer.

Finally, they show that over-expression of this gene is necessary for the growth of the hormone-independent prostate cancer cells.

"Interestingly," Wang says, "the UBE2C gene is also over-expressed in breast, lung, ovary, bladder, thyroid and esophageal cancers, suggesting that our findings could have wide application."

Funding from the National Cancer Institute and Department of Defense supported this research.